In previous studies, we have shown that endothelium-dependent vasodilation to acetylcholine and substance P is impaired in patients with essential hypertension. Animal studies have shown that in certain conditions with endothelial dysfunction, the abnormality might be specifically located at the level of intracellular signal transduction pathways. The purpose of this study was to determine whether such a selective abnormality in endothelial function may explain the impaired vascular responses of hypertensive patients. To this end, we studied 10 hypertensive patients (5 men; age 48plus/minus9 years) and 12 normal controls (6 men; 48plus/minus7 years). Subjects received intra-arterial administration of acetylcholine and bradykinin (endothelium-dependent vasodilators preferentially acting through different intracellular signal transduction pathways) and sodium nitroprusside (endothelium-independent vasodilator). Drugs were infused into the brachial artery and blood flow was measured noninvasively by strain gauge plethysmography. As shown before, the response to acetylcholine was significantly reduced in hypertensive patients compared to normal controls; however, no difference was observed in the response to sodium nitroprusside. Bradykinin produced a vasodilator response in both groups. However, this response was significantly reduced in the hypertensive patients compared to the controls. A significant correlation was found between the vascular responses to bradykinin and acetylcholine, while no correlation was observed between the response to sodium nitroprusside and either of the endothelium-dependent vasodilators. Thus, hypertensive patients have abnormal endothelium-dependent responses not only to acetylcholine but also to bradykinin. These findings indicate that the impaired endothelial function of hypertensive patients is not due to a specific abnormality of a single intracellular signal transduction pathway and suggest a more generalized abnormality of the vascular endothelium.